Breast cancer is the leading cause of cancer in women and only 10% of cases thought to be caused by inherited germline mutations, suggesting a strong role for the interaction between environmental stressors and genetic predisposition. The aim of this proposal is to characterize how breast carcinogenesis is modulated by psychological traits and social circumstances that cause stress over the life-span. In rats, fearful temperament, lack of reciprocal social support, and social isolation confer an increased risk for spontaneous tumorigenesis and early mortality. Greater than 40% of tumors are malignant ductal carcinomas or pre-malignant ductal carcinoma in situ (DCIS). It is hypothesized that the endogenous regulation of glucocorticoid release in response to stress partially mediates this effect by suppressing apoptosis in neoplastic cells. To determine which phases of the carcinogenic process are amenable to psychosocial modulation, female rats will be administered 7,12-dimethylbenz(a)anthracene (DMBA), a well- characterized chemical carcinogen known to initiate mammary tumorigenesis. A subset of rats will be sacrificed 8 days following DMBA administration, the start of a 2-week critical period for tumor promotion, to measure rates of apoptosis and proliferation in the mammary epithelium. Another subset will be maintained until 50% of the population has developed at least one reliably palpable mammary tumor. Standardized tumor initiation will reveal whether subsequent phases of the carcinogenic process can be modulated by psychological traits and social circumstances that predispose stress over the life-span. A second related study will examine the role of life-long psychosocial factors in mammary development. The degree to which developing mammary glands are exposed to pre-cyclic ovarian hormone dynamics is hypothesized to be a strong risk factor for mammary carcinogenesis. We will test whether psychological traits and social circumstances that cause life-long stress predispose a carcinogenic hormonal environment by (1) tracking the onset of estrous cycles and (2) characterizing mammary development from puberty to young adulthood. Together, these studies will offer new insights into the psychological and social regulation of breast cancer by testing whether psychosocial factors affect tumor development and growth, and do so through the endogenous regulation of hormones. As such, these studies will also allow an estimation of the proportion of the racial disparity in breast cancer that can be explained by social inequalities. [unreadable] [unreadable] [unreadable] [unreadable]